Upper gastrointestinal symptoms arising from diabetic gastropathy, and gastroparesis, the irreversible, end-stage form of gastropathy, have been reported in 30-60% of patients after approximately 10 years of both insulin-dependent and non-insulin-dependent diabetes mellitus. These gastric motor abnormalities can seriously affect the patients' quality of life, may affect glycemic control and can occasionally result in incapacitating symptoms like malnutrition, water and electrolyte imbalance or even aspiration. Most basic and clinical scientists view these complications of diabetes as a manifestation of autonomic neuropathy but their exact pathomechanism remains unclear. In the present proposal we offer a novel hypothesis. Recently, interstitial cells of Cajal (ICC), a mesenchymal cell type residing in the myenteric region (ICC-MY) and within smooth muscle layers (ICC-IM) of the stomach, have been identified as pacemakers and mediators of neurotransmission, respectively. Because both functions are seriously affected in diabetic gastropathy, it is possible that disruption of ICC networks could underlie some of the pathological changes characteristic of this disease. Our published work and additional preliminary studies using non-obese, spontaneously diabetic (NOD) mice, as well as a recent report about the human gastrointestinal complications of diabetes (He et al., Gastroenterology 121: 427-434, 2001) support the validity of this hypothesis. Thus, NOD mice offer an exciting new animal model for studies of diabetic gastropathy. In this project we plan to characterize and use this model to: (1) study how networks of gastric ICC are altered in diabetic gastroparesis and how alterations in ICC-MY number and distribution could lead to gastric arrhythmias and impaired gastric emptying; (2) to investigate whether ICC depletion in the stomach of diabetic NOD mice is due to hyperglycemia or hypoinsulinemia and to study the mechanisms by which these factors influence ICC phenotype and function; and (3) to examine what cellular mechanisms (e.g. apoptosis, necrosis or transdifferentiation) lead to the reduction of ICC in the distal stomach. The proposed experiments could provide the basic concepts needed for the development of novel, more effective treatment options for patients with diabetic gastropathy.